USP38

USP38 is a ubiquitin-specific protease that deubiquitinates a remarkably broad array of substrates to regulate innate immunity, inflammation, chromatin state, DNA damage repair, hypoxia signaling, and cardiac electrophysiology. Its catalytic activity cleaves polyubiquitin chains of multiple linkage types—K33 from TBK1 to license K48-mediated degradation and suppress type I IFN signaling (PMID:27692986), K27 from IL-33R to drive autophagic receptor turnover (PMID:35238669), K63 from HDAC1 and HDAC3 to maintain histone deacetylase stability and promote NHEJ-mediated DNA repair (PMID:31874856, PMID:32404892), K48 from JunB and β-catenin to stabilize transcription factors (PMID:30224386, PMID:41407221), and K11 from HIF1α to activate hypoxia-responsive transcription (PMID:38072059). USP38 also functions as a histone deubiquitinase that removes monoubiquitin from H2B-K120, facilitating KDM5B recruitment and repression of pro-inflammatory cytokine genes (PMID:33240782). USP38 undergoes ADAR-facilitated auto-deubiquitylation to regulate its own stability, and in the heart, cardiac-specific deletion attenuates TAK1/NF-κB– and CaMKII-dependent inflammatory remodeling and ventricular arrhythmia susceptibility across multiple disease models (PMID:39303916, PMID:37903290, PMID:40482978).

1. 2016 High

   The discovery that USP38 cleaves K33-linked polyubiquitin from TBK1 at K670 to permit K48-linked ubiquitination and degradation established USP38 as a linkage-selective deubiquitinase that terminates type I IFN signaling, answering how the NLRP4 signalosome resolves TBK1 activation.

   Evidence In vitro DUB assay, linkage-specific ubiquitin analysis, KO/KD with IFN readout, site-directed mutagenesis at K670

   PMID:27692986

   Open questions at the time

   • Whether K33 specificity extends to other substrates was unknown
   • Structural basis for K33 selectivity unresolved
   • Physiological consequences of USP38 loss in viral infection models not tested
2. 2018 High

   Identification of JunB and LSD1 as USP38 substrates demonstrated that USP38 stabilizes transcription factors and epigenetic regulators beyond innate immunity, establishing its role in T-helper cell differentiation and proliferation.

   Evidence Co-IP, in vitro DUB assay, USP38-KO mice in OVA/HDM asthma models (JunB); Co-IP, Western blot, colony formation assays (LSD1)

   PMID:30224386 PMID:30497519

   Open questions at the time

   • Whether USP38-JunB axis operates in non-Th2 immune contexts unclear
   • LSD1 stabilization demonstrated in single lab without in vivo validation
3. 2019 High

   The finding that USP38 removes K63-linked ubiquitin from HDAC1 to promote H3K56 deacetylation and efficient NHEJ revealed a chromatin-regulatory axis linking USP38 to DNA damage repair.

   Evidence In vitro DUB assay, KO mice with irradiation sensitivity, NHEJ reporter assay, γH2AX/53BP1 foci analysis

   PMID:31874856

   Open questions at the time

   • Whether USP38 also regulates homologous recombination not tested
   • No structural model of USP38-HDAC1 interaction
4. 2020 High

   Demonstration that USP38 deubiquitinates H2B-K120 monoubiquitin and stabilizes KDM5B at inflammatory gene promoters established a dual chromatin-remodeling mechanism controlling IL-6 and IL-23α transcription, while parallel work identified HDAC3 as an additional K63-linked substrate in colorectal cancer stem cells.

   Evidence ChIP, in vitro DUB assay, KO mice in endotoxin shock/colitis models (H2B/KDM5B); Co-IP, denaturing ubiquitination assay (HDAC3)

   PMID:32404892 PMID:33240782

   Open questions at the time

   • Whether H2B-K120 deubiquitination is direct or KDM5B-dependent was not fully dissected
   • HDAC3 stabilization awaits in vivo validation
5. 2021 Medium

   Discovery of c-Myc stabilization via FBW7α inhibition and antiviral deubiquitination of ZIKV envelope protein expanded USP38's substrate repertoire to oncoprotein regulation and host-pathogen interactions.

   Evidence Co-IP, polyubiquitination assay, cell proliferation assay (c-Myc/FBW7α); Co-IP, catalytic mutant analysis, viral infection assay (ZIKV E protein)

   PMID:34102342 PMID:34696459

   Open questions at the time

   • c-Myc stabilization shown in single lab without in vivo tumor model
   • Antiviral specificity beyond ZIKV unknown
   • No independent replication of FBW7α interaction
6. 2022 High

   Identification of IL-33R K27-linked deubiquitination by USP38 driving autophagic receptor degradation established a new linkage specificity and an in vivo anti-inflammatory role in pulmonary fibrosis.

   Evidence Co-IP, KO mice with pulmonary fibrosis and inflammation models, site-specific ubiquitination at K511, in vitro DUB assay

   PMID:35238669

   Open questions at the time

   • Whether USP38 targets other K27-linked substrates not explored
   • Mechanism coupling deubiquitination to selective autophagy not defined
7. 2023 Medium

   Cardiac-specific KO and transgenic models revealed that USP38 promotes TAK1/NF-κB-mediated inflammatory remodeling after MI, while HIF1α K11-linked deubiquitination at K769 established USP38 in hypoxia signaling—together broadening USP38's physiological impact to cardiovascular disease.

   Evidence Cardiac-conditional KO/TG mice with electrophysiology and histology (cardiac); Co-IP, site-specific ubiquitination assay, KO with hypoxia gene readout (HIF1α)

   PMID:37903290 PMID:38072059

   Open questions at the time

   • Direct cardiac substrate mediating TAK1/NF-κB activation not identified
   • HIF1α stabilization shown in single lab without independent confirmation
   • Whether cardiac phenotype is cell-autonomous unclear
8. 2024 Medium

   Discovery that USP38 auto-deubiquitylates to regulate its own stability, enhanced by ADAR in an RNA editing-independent manner, provided the first insight into USP38 self-regulation, while NOX4 deubiquitination linked USP38 to oxidative stress-mediated arrhythmogenesis.

   Evidence Co-IP, denaturing ubiquitination assay, ADAR-KD rescue (auto-DUB); cardiac-specific KO/TG mice, Co-IP, electrophysiology (NOX4)

   PMID:39303916 PMID:40482978

   Open questions at the time

   • Structural basis of ADAR-USP38 interaction unknown
   • Whether ADAR regulation of USP38 occurs in non-cancer contexts not tested
   • NOX4 deubiquitination linkage type not specified
9. 2025 Medium

   A burst of substrate discoveries—MDM2/p53, PTEN, TLR4, β-catenin, PLK1, MCT1, BIRC5, and HIPK2—cemented USP38 as a pleiotropic DUB controlling ferroptosis, PI3K/Akt signaling, cardiac protection, and tumor biology through stabilization of diverse client proteins.

   Evidence Multiple cardiac-specific KO/TG models, Co-IP and ubiquitination assays, ferroptosis/apoptosis readouts, in vivo tumor models across multiple single-lab studies

   PMID:39642563 PMID:39987355 PMID:40151769 PMID:40189893 PMID:40252884 PMID:41166987 PMID:41275979 PMID:41407221 PMID:41854204

   Open questions at the time

   • Most substrates identified by single labs without independent replication
   • No systematic selectivity analysis explaining how USP38 recognizes such diverse substrates
   • Relative physiological importance of individual substrates in specific tissues not ranked

• How USP38 achieves linkage-specific and substrate-specific deubiquitination across K33, K27, K63, K48, and K11 chains with no known adaptor specificity domain, and which substrates are physiologically rate-limiting in each tissue context, remain central unresolved questions.
• No crystal or cryo-EM structure of USP38 catalytic domain or substrate complexes
• No unbiased proteomics-based substrate catalogue
• Relative contributions of individual substrates to in vivo phenotypes not dissected